Azeto-imidazo-diazepines

ABSTRACT

There is presented imidazodiazepines of the formula ##STR1## wherein A together with the two carbon atoms denoted as α and β is the group ##STR2## R 1  is hydrogen, lower alkyl, lower alkoxymethyl, halogen, nitro or a group of the formula --COOR 4 , R 2  is hydrogen, trifluoromethyl or halogen, R 3  is hydrogen, trifluoromethyl, halogen or lower alkyl, R 4  is methyl, ethyl or isopropyl and X is an oxygen or sulphur atom and the carbon atom denoted as γ has the (S)-- or (R,S)-- configuration, 
     and their pharmaceutically acceptable acid addition salts. 
     The compounds are useful in the antagonization of the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of therapy, for example, of schistosomicidally-active, 1,4-benzodiazepines. Also provided are methods to produce the above compounds.

This is a division, of application Ser. No. 349,405 filed Feb. 16, 1982,now U.S. Pat. No. 4,352,816, granted Oct. 5, 1982.

DESCRIPTION OF THE INVENTION

The present invention is concerned with imidazodiazepines. Moreparticularly, the invention is concerned with imidazodiazepines of theformula ##STR3## wherein A together with the two carbon atoms denoted asα and β is the group ##STR4## R¹ is hydrogen, lower alkyl, loweralkoxymethyl, halogen, nitro or a group of the formula --COOR⁴, R² ishydrogen, trifluoromethyl or halogen, R³ is hydrogen, trifluoromethyl,halogen or lower alkyl, R⁴ is methyl, ethyl or isopropyl and X is anoxygen or sulphur atom and the carbon atom denoted as γ has the (S)-- or(R,S)--configuration, and pharmaceutically acceptable acid additionsalts thereof.

Objects of the present invention are compounds of formula I andpharmaceutically acid addition salts thereof per se and aspharmaceutically active substances, the manufacture of these compoundsand intermediates for the manufacture of these compounds, medicamentscontaining a compound of formula I or a pharmaceutically acceptable acidaddition salt thereof and the manufacture of such medicaments.

The term "lower alkyl" denotes saturated hydrocarbon groups, which canbe straight-chain or branched-chain, containing at most 7, preferably atmost 4, carbon atoms such as methyl, ethyl, isopropyl, t-butyl and thelike. The term "lower alkoxymethyl" includes groups such asmethoxymethyl, ethoxymethyl and the like. The term "halogen" signifiesfluorine, chlorine, bromine and iodine.

R¹ preferably is hydrogen, chlorine or a group of the formula --COOR⁴ inwhich R⁴ preferably is ethyl. The symbol A preferably is group (a)hereinbefore: in this case R² preferably is hydrogen and R³ preferablyis hydrogen or chlorine. The symbol X preferably is an oxygen atom.

A quite especially preferred compound of formula I is ethyl(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate.

Other compounds of formula I which are especially preferred are:

Ethyl(R,S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate,

(S)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one,

ethyl(S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylateand

(S)-1-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one.

The imidazodiazepines of formula I and their pharmaceutically acceptableacid addition salts can be manufactured in accordance with the inventionby

(a) Reacting a compound of the formula ##STR5## wherein A is as aboveand Z is a leaving group, in the presence of a base with anisocyanoacetic ester of the formula

    CN--CH.sub.2 --COOR.sup.4                                  III

wherein R⁴ is as above, or

(b) treating a compound of the formula ##STR6## wherein A and R⁴ are asabove, with a formylating agent, or

(c) dehydrogenating a compound of the formula ##STR7## wherein A and R⁴are as above or

(d) replacing the amino group in an amino compound of the formula##STR8## wherein A and X are as above by a halogen atom or by the nitrogroup, or

(e) oxidizing the amino group in an amino compound of formula VII aboveto the nitro group, or

(f) decarboxylating a carboxylic acid of the formula ##STR9## wherein Aand X are as above or

(g) halogenating a compound of the formula ##STR10## wherein A and X areas above in the imidazole ring, or

(h) cleaving off under reductive conditions the leaving group denoted byZ' in a compound of the formula ##STR11## wherein A and X are as above,R⁵ is hydrogen or lower alkyl and Z' is a leaving group, or

(i) trans-esterifying a compound of the formula ##STR12## wherein A andX are as above and R⁶ is lower alkyl, or

(j) converting the carbonyl group in a compound of the formula ##STR13##wherein R¹ and A are as above, into the thiocarbonyl group, or

(k) etherifying a compound of the formula ##STR14## wherein A, X and Z'are as above with an alkylating agent yielding a lower alkyl group inthe case of a compound of formula XVI or with a lower alcohol in thecase of a compound of formula IXa, and

(l) if desired, converting a compound of formula I obtained into apharmaceutically acceptable acid addition salt.

In accordance with process variant (a), compounds of formula I can bemanufactured from compounds of formula II and isocyanoacetic esters offormula III. The leaving group denoted by Z in formula II is, forexample, a readily cleavable phosphinyl group, e.g. a group of theformula ##STR15## wherein R⁷ is lower alkyl and R⁸ and R⁹ each are loweralkyl, allyl, phenyl or substituted phenyl or R⁸ and R⁹ together withthe nitrogen atom are an unsubstituted or substituted heterocyclic ringwith 3-8 members (such as morpholine), a halogen atom, an alkylthiogroup, an aralkylthio group, a N-nitrosoalkylamino group, an alkoxygroup, a mercapto group and the like (when Z is a mercapto group, thenthe corresponding compound of formula II is the iminothiol form of thecorresponding thiolactam). The reaction of a compound of formula II witha compound of formula III is carried out in an inert solvent such asdimethylformamide, hexamethylphosphoric acid triamide, dimethylsulphoxide, tetrahydrofuran or any other suitable organic solvent and inthe presence of a base which is sufficiently strongly basic to form theanion of the isocyanoacetic ester of formula III. Suitable bases arealkali metal alkoxides such as sodium methoxide or potassium t-butoxide,alkali metal hydrides such as sodium hydride, alkali metal amides suchas lithium amide or lithium diisopropylamide, tertiary amines such astriethylamine, and the like. The reaction is conveniently carried out ata temperature between about -40° C. and about room temperature.

In accordance with process variant (b), compounds of formula I can bemanufactured by treating compounds of formula IV with a formylatingagent. Suitable formylating agents for this process variant are loweralkyl esters of orthoformic acid and technical equivalents thereof, forexample ortho-amides such as N,N-dimethylformamide dimethyl acetal,N,N,N',N',N",N"-hexamethylmethanetriamine and the like. The reaction ofa compound of formula IV with a formylating agent is convenientlycarried out in the presence of an acid catalyst, for example an organicor inorganic acid such as p-toluenesulphonic acid, phosphoric acid andthe like, and at room temperature or at a temperature above roomtemperature, for example between about 25° and about 150° C.

In accordance with process variant (c), compounds of formula I can bemanufactured by dehydrogenating compounds of formula V or VI. Preferredreagents for this dehydrogenation include manganese dioxide,palladium-on-carbon and elemental oxygen, with atmospheric oxygen beingsufficient. However, potassium permanganate, for example, can also beused. Solvents in which this dehydrogenation can be carried out includechlorinated hydrocarbons such as methylene chloride and chloroform,aromatic hydrocarbons, dimethylformamide etc. The dehydrogenation iscarried out at room temperature or at a temperature above roomtemperature, conveniently between about 25° and about 200° C.

In accordance with process variant (d), compounds of formula I in whichR¹ is halogen or nitro can be manufactured by replacing the amino groupin a compound of formula VII by a halogen atom or by the nitro group.Conveniently, the amino compound of formula VII is converted into acorresponding diazonium salt and this is reacted, optionally withoutprevious isolation, with a nitrite such as sodium nitrite or with ahalide (e.g. with a chloride or bromide) in the presence of a copper (I)salt. The presence of a copper (I) salt is not necessary for themanufacture of the corresponding iodides. Corresponding fluorides areconveniently manufactured via a corresponding diazoniumtetrafluoroborate, for example by irradiation with UV light. Thesereactions are preferably carried out in aqueous solutions attemperatures of about -10° C. to about room temperature.

In accordance with process variant (e), compounds of formula I in whichR¹ is nitro can also be manufactured by oxidizing an amino compound offormula VII. Suitable oxidizing agents are, for example, peracids suchas peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid andperbenzoic acid, and the like. As solvents there come intoconsideration, depending on the oxidizing agent used, carboxylic acidssuch as acetic acid etc, halogenated hydrocarbons such as methylenechloride, chloroform, 1,2-dichloroethane etc, or the like. As a rule,the oxidation is carried out at a temperature of about 0° C. to aboutroom temperature.

In accordance with process variant (f), compounds of formula I in whichR¹ is hydrogen can be manufactured by decarboxylating carboxylic acidsof formula VIII. This decarboxylation is conveniently carried out by dryheating the carboxylic acid of formula VIII, which may be crude, totemperatures of about 150° C. to about 400° C., the temperaturedepending on the melting point of the particular compound of formulaVIII used.

In accordance with process variant (g), compounds of formula I in whichR¹ is halogen can be manufactured by halogenating compounds of formulaIa. Suitable halogenating agents are, for example, N-chlorosuccinimide,N-bromosuccinimide, N-chloroacetamide, N-bromoacetamide and elementaliodine. As solvents there are conveniently used inert organic solvents,for example halogenated hydrocarbons such as methylene chloride,1,2-dichloroethane, chloroform and the like, dimethylformamide,dimethylacetamide, acetonitrile, ethers such as diethyl ether,tetrahydrofuran, dioxan and the like, etc. The halogenation can becarried out in a temperature range of about 0° C. to about 120° C.depending on the solvent used.

In accordance with process variant (h), compounds of formula I in whichR¹ is lower alkyl can be manufactured by cleaving off under reductiveconditions the leaving group denoted by Z' in a compound of formula IX.This process variant is carried out according to methods known per se,the choice of the suitable leaving group denoted by Z' as well as thedetermination of the conditions suitable for the cleavage, under whichother structural elements present in the molecule should not beaffected, presenting no difficulties to a person skilled in the art.Especially suitable leaving groups for the present process variant are,for example, halogen atoms such as chlorine, bromine and iodine whichcan be cleaved off readily under hydrogenolytic conditions, for exampleby treatment with elemental hydrogen in the presence of a suitablecatalyst (e.g. palladium/carbon, Raney-nickel, etc.) in an inert organicsolvent. Suitable solvents are, for example, alcohols such as methanol,ethanol and isopropanol, ethers such as diethyl ether, tetrahydrofuran,dioxan and dimethoxyethane, and the like. Depending on the reactivity ofthe catalyst used the cleavage is carried out at pressures of aboutnormal pressure to about 300 bar and at temperatures of about roomtemperature to about 150° C.

In accordance with process variant (i), compounds of formula I can bemanufactured by trans-esterifying compounds of formula Ib, i.e. byreplacing the alkyl group denoted by R⁶ in a compound of formula Ib bythe desired group R⁴.

This trans-esterification is carried out in a manner known per se byreacting a compound of formula Ib with an alcohol corresponding to thedesired group denoted by R⁴ (i.e. with methanol, ethanol or isopropanol)at room temperature or while heating to a temperature of about 25° to150° C. Preferably, the trans-esterification is carried out in thepresence of a base, with potassium cyanide or similar weak bases beingespecially suitable in the present case. As the base there is, however,also suitable the alcoholate corresponding to the desired group denotedby R⁴, for example, sodium methanolate, ethanolate or isopropanolate orthe corresponding potassium salt. As the solvent there is preferablyused the alcohol corresponding to the group denoted by R⁴ in the desiredcompound of formula I. However, the trans-esterification can also becarried out in an inert organic solvent, for example an aromatichydrocarbon such as benzene or xylene, an ether such as dioxan,tetrahydrofuran or ethyleneglycol dimethyl ether, dimethylformamide,dimethyl sulphoxide or the like. In this trans-esterification not onlycan a low boiling alcohol be replaced by a high boiling alcohol, butalso a high boiling alcohol can be replaced by a low boiling alcohol.

The trans-esterification can, however, also be carried out readily inseveral stages, for example, by hydrolyzing a compound of formula Ib tothe corresponding free carboxylic acid of formula VIII, preparing fromthis a reactive functional derivative (e.g. an acid chloride or thelike) and subsequently reacting this reactive carboxylic acid derivativewith the alcohol corresponding to the significance of R⁴ in the desiredcompound of formula I.

In accordance with process variant (j), compounds of formula Ic can beconverted into corresponding compounds of formula I in which X is asulphur atom by treatment with a sulphurizing agent, which can becarried out in a manner known per se. For example, the sulphurizingagent can be phosphorus pentasulphide, this being preferably used inexcess and the reaction being advantageously carried out in an inertorganic solvent such as dioxan, methylene chloride or the like in thepresence of triethylamine at a temperature of about 50° C. up to thereflux temperature of the reaction mixture. Other suitable sulphurizingagents are compounds such as2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulphide; suchsulphurizing agents being used in approximately the calculated amountand the reaction being carried out in the presence of an inert solventsuch as toluene or xylene, conveniently at the reflux temperature of thereaction mixture, or in hexamethylphosphoric acid triamide at atemperature between about 60° and 110° C.

In accordance with process variant (k), compounds of formula I in whichR¹ is lower alkoxymethyl can be manufactured by etherifying an alcoholof formula XVI with an alkylating agent yielding a lower alkyl group oretherifying a compound of formula IXa with a lower alcohol. Thisetherification is carried out in an inert organic solvent such asdimethylformamide, hexamethylphosphoric acid triamide, dimethylsulphoxide, tetrahydrofuran or any other suitable organic solvent and inthe presence of a base which is sufficiently strongly basic to form thecorresponding alcoholate from the alcohol of formula XVI or from thelower alcohol. Suitable bases are, for example, alkali metal hydridessuch as sodium hydride, alkali metals such as sodium and alkali metalamides such as lithium amide and lithium diisopropylamide. Suitablealkylating agents are, for example, alkyl halides such as methyl iodide,ethyl iodide and ethyl bromide and dialkyl sulphates such as dimethylsulphate and diethyl sulphate. This etherification is convenientlycarried out at a temperature between about 0° C. and about 50° C.

In accordance with process (l), compounds of formula I can be convertedinto pharmaceutically acceptable acid addition salts. The manufacture ofsuch pharmaceutically acceptable acid addition salts is carried outaccording to generally used methods. The salts provided by the presentinvention are salts formed with inorganic acids and organic acids; forexample, hydrochlorides, hydrobromides, sulphates, methanesulphonates,p-toluenesulphonates, oxalates and the like.

The compounds of formula II used as starting materials can be preparedstarting from compounds of the general formula ##STR16## wherein A is asabove according to methods which are known per se; see, for example,Belgian Patent Specifications Nos. 802 233, 833 249 and 865 653, U.S.Pat. No. 3,681,341 and J. Org. Chemistry 29, 231 (1964), incorporatedherein for reference purposes.

Various Examples hereinafter contain detailed information concerning thepreparation of compounds of formula II from compounds of formula X.

The compounds of formula X, in turn, can be prepared readily accordingto methods known per se; for example, by reacting a correspondingcarboxylic acid anhydride of the formula ##STR17## wherein A is as abovewith (L)- or (D,L)-azetidinecarboxylic acid.

It is also possible to react a compound of the formula ##STR18## whereinA and R⁶ are as above with a reactive derivative of a carboxylic acid ofthe formula ##STR19## wherein Y is a protecting group, for example acarboxylic acid chloride or the like. After removing the protectinggroup denoted by Y from a thus-obtained compound of the formula##STR20## wherein R⁶, A and Y are as above and cyclizing the substanceobtained (e.g. by heating to temperatures of about 100° to about 300° C.for a short time), there is obtained a compound of formula X.

The compounds of formulae IV, V and VI can be prepared according tomethods known per se (see Belgian Patent Specifications Nos. 883 248 and839 364), incorporated herein for reference, starting from compounds offormula II in accordance with Formula Scheme 1 hereinafter in which A,R⁴ and Z are as above. ##STR21##

The amino compounds of formula VII used as starting materials can beprepared, for example, in a manner known per se from the carboxylic acidazides of the formula ##STR22## wherein A and X are as above, forexample, by treating such an azide with an alcohol (e.g. methanol,ethanol, benzyl alcohol or the like) at an elevated temperature andhydrolyzing the urethane obtained. In a preferred embodiment, benzylalcohol is used and the benzylurethane obtained is cleavedhydrogenolytically.

The carboxylic acid azides of formula XV can be prepared, for example,by treating a carboxylic acid ester of formula Ib with hydrazine andreacting the carboxylic acid hydrazide obtained with sodium nitrite inthe presence of an acid such as acetic acid.

The compounds of general formula VIII used as starting materials can bereadily prepared by hydrolyzing carboxylic acid esters of formula Ib.Conveniently, the hydrolysis is carried out in basic aqueous solution,for example in aqueous sodium hydroxide, optionally in the presence of asolubilizer (e.g. methanol, ethanol, tetrahydrofuran, dioxan or thelike). If the compound of formula Ib is a t-alkyl ester (e.g. a t-butylester), then the hydrolysis is conveniently carried out under acidicconditions; for example, using trifluoroacetic acid, aqueous mineralacids or the like.

The compounds of formula IX used as starting materials are readilyaccessible from carboxylic acid esters of formula Ib in accordance withFormula Scheme 2 hereinafter in which A, X, Z' and R⁶ are as above andR⁵¹ is lower alkyl: ##STR23##

The reduction of a compound of formula Ib to give an alcohol of formulaXVI is preferably carried out using a reducing agent such as lithiumborohydride in an inert organic solvent such as diethyl ether,tetrahydrofuran, dimethoxyethane or the like.

The preparation of a compound of formula XVII from an alcohol of formulaXVI is preferably carried out using a mild oxidizing agent such asmanganese dioxide or the like in an inert organic solvent such asmethylene chloride, chloroform or the like.

The compounds of formula XVIII can be prepared by reacting a compound offormula XVII with a metal-organic compound yielding the group R⁵¹according to methods which are generally known and familiar to anyperson skilled in the art. Preferred metal-organic compounds areGrignard compounds such as methyl-magnesium iodide, ethyl-magnesiumiodide, isopropyl-magnesium bromide, n-propyl-magnesium bromide,n-butyl-magnesium chloride and the like. Suitable solvents are etherssuch as diethyl ether, tetrahydrofuran, t-butyl methyl ether, mixturesthereof and the like. Conveniently, the reaction is carried out at theboiling point of the reaction mixture, although it can, however, also becarried out at a lower temperature (e.g. at room temperature).

The compounds of formula IX (i.e. formulae IXa and IXb) can be preparedfrom compounds of formula XVI or XVIII according to methods which aregenerally known and familiar to any person skilled in the art.Corresponding halides are obtained, for example, by treating compoundsof formula XVI or XVIII with halogenating agents such as thionylchloride, phosphorus oxychloride, phosphorus pentachloride, carbontetrabromide/triphenylphosphine and the like.

The compounds of formulae II, IV, V, VI, VII, VIII, IX and XVI used asstarting materials are novel and are likewise objects of the presentinvention.

The compounds of formula Ib in which R⁶ is not methyl, ethyl, isopropylor t-butyl are likewise an object of the present invention.

As mentioned earlier, the compounds of formula I are novel and haveextremely valuable pharmacodynamic properties. They exhibit only a lowtoxicity and it has been shown that they have a pronounced affinity tothe central benzodiazepine receptors and are capable of antagonizing thecentral-depressant, muscle relaxant, ataxic, blood pressure-lowering andrespiratory-depressant properties of 1,4-benzodiazepines which havetranquillizing activity.

The affinity of compounds of formula I to the central benzodiazepinereceptors was determined according to the method described in LifeScience 20, 2101-2110 (1977) and Science, 198, 849-851 (1977). Accordingto this method, the inhibition of the binding of tritiated diazepam atthe specific benzodiazepine receptors in the cerebral cortex by therespective test substances is ascertained. The IC₅₀ ("50% inhibitingconcentration") is that concentration of the respective test substancewhich brings about a 50 percent inhibition of the specific binding ofthe tritiated diazepam at the specific benzodiazepine receptors in thecerebral cortex.

One of the typical properties of 1,4-benzodiazepines, which havetranquillizing activity, in experimental animals is their pronouncedanticonvulsant activity which can be demonstrated, for example, in theknown and generally recognized pentetrazole test. This property was usedto evaluate the test described hereinafter which permits thedetermination of compounds which are capable of antagonizing the centralproperties of 1,4-benzodiazepines which have tranquillizing activity.

In this test, 5 mg/kg (i.p.) of diazepam (i.e. a supramaximal dosagewhich in the pentetrazole test on more than 900 mice protects allexperimental animals from convulsive attacks) were administered to mice1 hour before the pentetrazole (120 mg/kg i.p.) and the compound to betested was administered p.o. 15 minutes before the pentetrazole. Theantagonistic activity of the compounds investigated, i.e. their abilityto counteract the activity of the diazepam in the pentetrazole test, isdetermined by counting the mice which suffer convulsive attacks in thistest.

In the following Table there are presented the results which have beenobtained with representative members of the class of compound defined byformula I in the test previously described. The ED₅₀ value is given foreach of the compounds listed in the Table. The ED₅₀ is the amount oftest compound in mg/kg (p.o.) which in 50% of the animals counteractsthe diazepam effect in the above test. Moreover, the Table contains theIC₅₀ value (defined above) for all test compounds listed therein.

                  TABLE                                                           ______________________________________                                        Compound of formula I  IC.sub.50                                                                             ED.sub.50                                                                     Config-                                                                             in    in                                 A   R.sup.2                                                                             R.sup.3                                                                             R.sup.1    X   uration                                                                             nM/l  mg/kg p.o.                         ______________________________________                                        (a) H     H     --COOCH.sub.2 CH.sub.3                                                                   O   (R,S) 3.0   5.4                                (a) H     H     --COOCH.sub.2 CH.sub.3                                                                   O   (S)   1.3   3.7                                (a) H     H     Cl         O   (S)   37.0  6.9                                (a) H     Cl    --COOCH.sub.2 CH.sub.3                                                                   O   (S)   0.99  0.75                               (a) H     Cl    H          O   (S)   150   15.8                               ______________________________________                                    

As mentioned earlier, the compounds of formula I antagonize thecentral-depressant, muscle relaxant, ataxic, blood pressure-lowering andrespiratory-depressant properties of 1,4-benzodiazepines which havetranquillizing activity. The latter are in widespread use in therapy andare often administered in high dosages, so that the above-mentionedactivities can also appear strongly as side-effects. The compounds offormula I can be used as antidotes in the case of intoxications in whichexcessive intake of 1,4-benzodiazepines which have tranquillizingactivity is concerned. They are also suitable for shortening anaesthesiain surgery and in obstetrics induced by 1,4-benzodiazepines which havetranquillizing activity. In the case of neonatals, a possiblerespiratory depression, which deteriorates upon the administration of1,4-benzodiazepines which have tranquillizing activity to the mother,can be counteracted. The compounds of formula I can also be used tosuppress, in the case of 1,4-benzodiazepines which are used in otherfields of indication, the activities on the central nervous system whichare undesirable in such a case. Examples of such 1,4-benzodiazepineswhich can be used in other fields of indication are theschistosomicidally-active 1,4-benzodiazepines described in BritishPatent Specifications Nos. 1 444 529 and 1 474 305 such as(+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one.

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be used as medicaments, for example, in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally (e.g. in the form of tablets, coated tablets,dragees, hard and soft gelatine capsules, solutions, emulsions orsuspensions). The administration can, however, also be carried outrectally (e.g. in the form of suppositories) or parenterally (e.g. inthe form of injection solutions).

For the manufacture of tablets, coated tablets, dragees and hardgelatine capsules, the compounds of formula I and their pharmaceuticallyacceptable acid addition salts can be processed with pharmaceuticalinert inorganic or organic carriers. Examples of such carriers which canbe used for tablets, dragees and hard gelatine capsules are lactose,maize starch or derivatives thereof, talc, stearic acid or its saltsetc. Suitable carriers for soft gelatine capsules are, for example,vegetable oils, waxes, fats, semi-solid and liquid polyols etc. Suitablecarriers for the manufacture of solutions and syrups are, for example,water, polyols, saccharose, invert sugar, glucose and the like. Suitablecarriers for injection solutions are, for example, water, alcohols,polyols, glycerine, vegetable oils etc. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can also contain preserving agents,solubilizing agents, stabilizing agents, wetting agents, emulsifyingagents, sweetening agents, colouring agents, flavouring agents, saltsfor varying the osmotic pressure, buffers, coating agents orantioxidants. They can also contain still other therapeutically valuablesubstances.

As mentioned earlier, compounds of general formula I andpharmaceutically acceptable acid addition salts thereof can be used inaccordance with the invention in the control or prevention of illnesses,especially in the antagonization of the central-depressant, musclerelaxant, ataxic, blood pressure-lowering and respiratory-depressantproperties of 1,4-benzodiazepines which have tranquillizing activity. Inparticular, compounds of formula I can be used in combination with theschistosomicidally-active compounds mentioned above, for example, incombination with(+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one,in the control of schistosomiasis. In this case, the compounds offormula I on their pharmaceutically acceptable acid addition salts canbe administered before, simultaneously with or after the administrationor intake of 1,4-benzodiazepines which have tranquillizing activity. Ifthe compound of formula I or a pharmaceutically acceptable acid additionsalt thereof is administered simultaneously with the 1,4-benzodiazepinewhich has tranquillizing activity, then the administration can be as anad-hoc combination or in the form of a pharmaceutical combination whichcontains a compound of formula I or a pharmaceutically acceptable acidaddition salt thereof and a 1,4-benzodiazepine derivative which hastranquillizing activity; such pharmaceutical combinations are likewisean object of the present invention. The dosage of the compounds offormula I and their pharmaceutically acceptable acid addition salts canvary within wide limits and is, of course, fitted to the individualrequirements in each particular case. In general, a daily dosage ofabout 0.2 mg to about 500 mg should be appropriate.

As mentioned earlier, medicaments containing a compound of formula I ora pharmaceutically acceptable acid addition salt thereof are likewise anobject of the present invention as is a process for the manufacture ofsuch medicaments which comprises bringing one or more compounds offormula I or pharmaceutically acceptable acid addition salts thereofand, if desired, one or more other therapeutically valuable substancesinto a galenical administration form; in this connection reference isagain made to the pharmaceutical combinations mentioned above which arelikewise an object of the present invention. In particular,pharmaceutical combinations containing a compound of formula I and oneof the schistosomicidally-active compounds mentioned above, especially(+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one,are an object of the present invention. Such combinations are suitablefor the control of schistosomiasis.

In the following Examples, which illustrate the present invention inmore detail but in no way are intended to limit its extent, alltemperatures are given in degrees Centigrade.

EXAMPLE 1

(a) 11.3 g of (0.057 mol) of 6-chloroisatoic acid anhydride and 5.78 g(0.057 mol) of L-azetidinecarboxylic acid are heated to 125° for 2 hoursin 50 ml of dimethyl sulphoxide. Subsequently, the mixture is evaporatedto dryness in a high vacuum and the residue obtained is heated to 150°for 2 hours. By chromatography on silica gel using ethyl acetate for theelution there is obtained(S)-5-chloro-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dioneof melting point 225°-228°.

(b) A suspension of 1.30 g (29.8 mmol) of sodium hydride (55 percent oildispersion) in 40 ml of dry dimethylformamide is treated with 6.38 g (27mmol) of(S)-5-chloro-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dioneat -15° and the mixture is stirred at this temperature for 0.5 hour.Subsequently, the mixture is cooled to -35° and treated dropwise with4.8 ml (29.8 mmol) of diethylchlorophosphate.

In the meanwhile, a solution of 3.55 g (32.4 mmol) of potassiumt-butylate in 14 ml of dry dimethylformamide is cooled in anacetone/dry-ice bath, treated with 4.1 ml (32.4 mmol) of ethylisocyanoacetate and added dropwise at -10° to the mixture obtainedaccording to the preceding paragraph. The cooling bath is removed, themixture is stirred for about a further 15 minutes, neutralized withglacial acetic acid, poured into 100 ml of water and extracted threetimes with chloroform. The combined chloroform extracts are washed threetimes with water, dried over magnesium sulphate and evaporated. Thecrude product obtained is chromatographed on silica gel and subsequentlyrecrystallized from ethyl acetate. There is obtained ethyl(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylateof melting point 184°-185°.

EXAMPLE 2

(a) A mixture of 1.79 g (5.4 mmol) of ethyl(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylateand 0.324 g (8.1 mmol) of sodium hydroxide is treated with 8.5 ml ofwater and 27 ml of ethanol and heated to boiling under reflux for 30minutes. Subsequently, the mixture is neutralized with 8.1 ml of 1 Nhydrochloric acid, the ethanol is distilled off, the residue is dilutedwith about 70 ml of water and left to stand in an ice-bath for 1 hour.The precipitated material is filtered off under suction, washed withwater and dried. There is obtained(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylicacid of melting point 244°-245°.

(b) 0.92 g (3.0 mmol) of(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylicacid is heated with a bunsen burner until the gas evolution has ceased.The crude product is chromatographed on silica gel usingchloroform/methanol (9:1) for the elution. After recrystallization fromethyl acetate/hexane, there is obtained(S)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-oneof melting point 207°-208°.

EXAMPLE 3

(a) 16.3 g (0.1 mol) of isatoic acid anhydride and 10.1 g (0.1 mol) ofL-azetidinecarboxylic acid are heated to 115° for 2 hours in 50 ml ofdimethyl sulphoxide. Subsequently, the mixture is poured into 450 ml ofwater, cooled to 0° and the precipitated crystalline material isfiltered off. There is obtained(S)-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione ofmelting point 217°-218°.

(b) A suspension of 1.03 g (23.7 mmol) of sodium hydride (55 percent oildispersion) in 25 ml of dry dimethylformamide is treated with 4.0 g(19.8 mmol) of(S)-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10-(2H,9H)-dione at-10° to -20° and the mixture is stirred at this temperature for 45minutes. The mixture is subsequently treated dropwise at -35° with 3.2ml (19.8 mmol) of diethylchlorophosphate. The mixture is stirred at -20°for about a further 20 minutes.

In the meanwhile, a solution of 2.17 g (19.3 mmol) of potassiumt-butylate in 7 ml of dry dimethylformamide is cooled in anacetone/dry-ice bath, treated with 2.5 ml (19.8 mmol) of ethylisocyanoacetate and added dropwise at -15° to -10° to the mixtureobtained according to the preceding paragraph. The cooling bath isremoved, the mixture is neutralized after 15 minutes with glacial aceticacid, poured into 100 ml of water and extracted three times withchloroform. The chloroform extracts are washed three times with water,dried over magnesium sulphate and evaporated. The crude product obtainedis chromatographed on a silica gel column. After recrystallization fromethyl acetate, there is obtained ethyl(S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-a]imidazo[1,5-a][1,4-benzodiazepine-1-carboxylateof melting point 191°-194°.

EXAMPLE 4

(a) A suspension of 1.93 g (44.3 mmol) of sodium hydride (55 percent oildispersion) in 45 ml of dry dimethylformamide is treated at -10° to -20°with 7.78 g (38.5 mmol) of(S)-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione. Themixture is stirred at -20° to -10° for 1.25 hours, treated dropwise with7.2 ml (44.3 mmol) of diethylchlorophosphate at -35° and the mixture isstirred at this temperature for about a further 20 minutes.

In the meanwhile, a solution of 4.85 g (44.3 mmol) of potassiumt-butylate in 15 ml of dry dimethylformamide is cooled in anacetone/dry-ice bath, treated with 6.26 g (44.3 mmol) of t-butylisocyanoacetate and added dropwise at -15° to the mixture obtainedaccording to the preceding paragraph. The cooling bath is removed, themixture is stirred for a further 15 minutes, neutralized with glacialacetic acid, poured into 350 ml of water and extracted several timeswith chloroform. The chloroform extracts are washed three times withwater, dried over magnesium sulphate and evaporated. By chromatographyon silica gel using ethyl acetate/chloroform (1:3) for the elution andsubsequent recrystallization of the resulting material from ethylacetate/n-hexane there is obtained t-butyl(S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylateof melting point 185°-187°.

(b) 1.77 g (5.4 mmol) of t-butyl(S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c[imidazo[1,5-a][1,4]benzodiazepine-1-carboxylateare stirred in 14 ml of trifluoroacetic acid at 50° C. for 3 hours andat 65° for 3.5 hours. Subsequently, the mixture is evaporated to drynessand the residue is heated on a steam-bath for 2.5 hours in a highvacuum. The material is treated with ether, stirred for 1 hour whilecooling with ice, the solid material is filtered off under suction whileback-washing with ether and then dried. There is obtained(S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylicacid of melting point 232°.

(c) 1.3 g (4.8 mmol) of(S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylicacid are heated to 240° until the gas evolution ceases. Afterrecrystallization from ethyl acetate, there is obtained(S)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-oneof melting point 195°-197°.

EXAMPLE 5

0.54 g (2.4 mmol) of(S)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a[1,4]benzodiazepin-9-oneand 0.32 g (2.4 mmol) of N-chlorosuccinimide are treated with 10 ml ofdimethylformamide and the mixture is stirred at 90° for 40 minutes. Themixture is poured into 50 ml of water and extracted four times withchloroform. The combined chloroform extracts are washed three times withwater, dried over magnesium suphate and evaporated. The crude product ischromatographed on silica gel using chloroform/methanol (19:1) for theelution and subsequently recrystallized from ethyl acetate. There isobtained(S)-1-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-oneof melting point 210°-214°.

EXAMPLE 6

(a) 2.3 g (22.8 mmol) of azetidine-2-carboxylic acid and 3.72 g (22.8mmol) of isatoic acid anhydride are treated with 20 ml of dimethylsulphoxide, the mixture is stirred at 110° for 2 hours, subsequentlypoured into 250 ml of water and stirred for a further 2 hours. Theprecipitated material is filtered off under suction, washed with waterand recrystallized from ethanol. There is obtained(R,S)-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione ofmelting point 250°-252°.

(b) 3.15 g (15.6 mmol) of(R,S)-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione areadded to a suspension of 0.82 g (18.7 mmol) of sodium hydride (55percent oil dispersion) in 25 ml of dry dimethylformamide. The mixtureis stirred for 30 minutes and subsequently treated dropwise at -35° with3 ml (18.7 mmol) of diethylchlorophosphate.

In the meanwhile, a solution of 2.05 g (18.7 mmol) of potassiumt-butylate in 7 ml of dry dimethylformamide is cooled in anacetone/dry-ice bath, treated with 2.4 ml (18.7 mmol) of ethylisocyanoacetate and added dropwise at -20° to -10° to the mixtureobtained according to the preceding paragraph. Subsequently, the coolingbath is removed, the mixture is neutralized at room temperature withglacial acetic acid, poured into 200 ml of water and extracted fourtimes with chloroform. The chloroform extracts are washed three timeswith water, dried over magnesium sulphate and evaporated. Bychromatography on a silica gel column using ethyl acetate for theelution and subsequent recrystallization from ethyl acetate there isobtained ethyl(R,S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylateof melting point 153°-154°.

Ethyl(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate(active substance A) can be used as the active substance for themanufacture of pharmaceutical preparations as illustrated in Examples Ato G:

EXAMPLE A

Tablets containing the following ingredients are manufactured in theusual manner:

    ______________________________________                                                         mg/tablet                                                    ______________________________________                                        Active substance A 1                                                          Lactose            103                                                        Maize starch       25                                                         Microcrystalline cellulose                                                                       70                                                         Magnesium stearate 1                                                          Total              200                                                        ______________________________________                                    

EXAMPLE B

Capsules containing the following ingredients are manufactured:

    ______________________________________                                                       mg/capsule                                                     ______________________________________                                        Active substance A                                                                             1                                                            Lactose          164                                                          Maize starch     30                                                           Talc             5                                                            Total            200                                                          ______________________________________                                    

The active substance, lactose and maize starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer, the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into hard gelatine capsules.

EXAMPLE C

Injection solutions containing the following ingredients aremanufactured:

    ______________________________________                                                         Per ml                                                       ______________________________________                                        Active substance A      0.5    mg                                             Benzyl alcohol          0.015  ml                                             Propyleneglycol         0.4    ml                                             Ethanol (95 percent)    0.1    ml                                             Sodium benzoate         48.8   mg                                             Benzoic acid            1.2    mg                                             Water for injection q.s. ad                                                                           1.0    ml                                             ______________________________________                                    

For the manufacture of 10 000 ml of injection solution, 5 g of theactive substance are dissolved in 150 ml of benzyl alcohol and 4000 mlof propyleneglycol and 1000 ml of ethanol are added thereto. Then, 12 gof benzoic acid are dissolved in the above mixture and there is addedthereto a solution of 488 g of sodium benzoate in 300 ml of water forinjection. The solution obtained is brought up to a volume of 10 000 mlby addition of water for injection, filtered and filled into ampoules ofsuitable size; the residual volume of the ampoules is filled withnitrogen, the ampoules are sealed and sterilized for 30 minutes in anautoclave at 0.7 atmosphere.

EXAMPLE D

Suppositories containing the following ingredients are manufactured:

    ______________________________________                                                         g/suppository                                                ______________________________________                                        Active substance A 0.001                                                      Cocoa butter (m.p. 36-37°)                                                                1.255                                                      Carnauba wax       0.044                                                      Total              1.3                                                        ______________________________________                                    

The cocoa butter and carnauba wax are melted in a glass or steel vessel,mixed thoroughly and cooled to 45°. Thereupon, there is added theretothe finely powdered active substance and the mixture is stirred until itis completely dispersed. The mixture is poured into suppository mouldsof suitable size, left to cool, the suppositories are removed from themoulds and packed individually in wax paper or metal foil.

EXAMPLE E

Capsules containing the following ingredients are manufactured:

    ______________________________________                                                             mg/capsule                                               ______________________________________                                        Active substance A     20.0                                                   (+)-5-(o-Chlorophenyl)-1,3-dihydro-3-                                         methyl-7-nitro-2H--1,4-benzodiazepin-                                         2-one (active substance B)                                                                           30.0                                                   Lactose (crystalline)  100.0                                                  Maize starch (white)   27.5                                                   Talc                   10.0                                                   Magnesium stearate     2.5                                                    Total                  190.0                                                  ______________________________________                                    

The two active substances are mixed well with the adjuvants and 190.0 mgof the mixture are filled into interlocking capsules of suitable size.

EXAMPLE F

Tablets containing the following ingredients are manufactured:

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        Active substance A     10.0                                                   (+)-5-(o-Chlorophenyl)-1,3-dihydro-3-                                         methyl-7-nitro-2H--1,4-benzodiazepin-                                         2-one (active substance B)                                                                           30.0                                                   Lactose (powdered)     15.0                                                   Maize starch (white)   19.5                                                   Povidon K30            3.5                                                    Maize starch (white)   10.0                                                   Magnesium stearate     2.0                                                    Total                  90.0                                                   ______________________________________                                    

The two active substances, the powdered lactose and the first portion ofwhite maize starch are mixed and sieved. This mixture is moistened witha solution of the Povidon K30 in water, kneaded, granulated, dried andsieved. The second portion of white maize starch and the magnesiumstearate are added to the granulate. After mixing, the mass obtained ispressed to tablets weighing 90 mg.

EXAMPLE G

Tablets containing the following ingredients are manufactured:

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        Active substance A     30                                                     (+)-5-(o-Chlorophenyl)-1,3-dihydro-3-                                         methyl-7-nitro-2H--1,4-benzodiazepin-                                         2-one                  30                                                     Lactose (powdered)     22                                                     Maize starch (white)   22                                                     Povidon K30            6                                                      Maize starch (white)   16                                                     Magnesium stearate     4                                                      Total                  130                                                    ______________________________________                                    

The two active substances, the powdered lactose and the first portion ofwhite maize starch are mixed and sieved. This mixture is moistened witha solution of the Povidon K30 in water, kneaded, granulated, dried andsieved. The second portion of white maize starch and the magnesiumstearate are added to the granulate. After mixing, the mass obtained ispressed to tablets weighing 130 mg.

What is claimed:
 1. A compound of the formula ##STR24## wherein Atogether with the two carbon atoms denoted as α and β is the group##STR25## wherein R² is hydrogen, trifluoromethyl or halogen; R³ ishydrogen, trifluoromethyl, halogen or lower alkyl and X is an oxygen orsulphur atom.
 2. The compound:(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-aceto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylicacid.